From worst-case to reality - Case studies illustrating tiered refinement of consumer exposure to cosmetic ingredients.

Consumer exposure to cosmetic ingredients is estimated in a tiered manner. Simple Tier1 deterministic aggregate exposure modelling generates a worst case estimate of exposure. Tier1 assumes that a consumer uses all cosmetic products concomitantly daily, at maximum frequency, and products always contain the ingredient at the maximum allowed % w/w concentration. Refining exposure assessment from worst case to more realistic estimates uses evidence from surveys of actual use levels of ingredients and Tier2 probabilistic models, where distributions of consumer use data can be applied. In Tier2+ modelling, occurrence data provides evidence of products on the market actually containing the ingredient. Three case studies are presented using this tiered approach to illustrate progressive refinement. The scale of refinements from Tier1 to Tier2+ modelling for the ingredients, propyl paraben, benzoic acid and DMDM hydantoin were: 0.492 to 0.026; 1.93 to 0.042 and 1.61 to 0.027 mg/kg/day exposure dose. For propyl paraben, moving from Tier1 to Tier2+ represents a refinement from 49-fold to 3-fold overestimate of exposure when compared to a maximum estimate of 0.01 mg/kg/day exposure seen in human studies. Such refinements from worst case to realistic levels of exposure estimation can be critical in the demonstration of consumer safety.

Macrophage culture as a suitable paradigm for evaluation of synthetic vitreous fibers.

The ultimate goal of toxicologic investigation of synthetic vitreous fibers (SVFs) is to provide essential input for the assessment of human risk to their exposure. Toxicity of mineral fibers is usually evaluated by testing biopersistence in rodent model. However, a cellular model would be much appreciated in order to reduce, refine, and replace animal models. Pulmonary disorders triggered by inhalation of occupational or environmental mineral particulates can be the endpoints of a chronic inflammatory process in which alveolar macrophages (AMs) play a crucial role. Depending on the type of SVF involved, phagocytosis of fiber leads to activation of macrophages, resulting in release of fiber components and potent mediators, such as reactive oxygen or nitrogen species and cytokines. As a matter of fact, macrophages should be the cells of choice since SVF toxicity is the consequence of fibers and alveolar macrophages interaction. Today, monocytes and macrophages culture are firmly established as a paradigm in toxicology when several endpoints are assayed in macrophages: (1) fiber durability, (2) fiber surface changes, (3) oxidative stress and genotoxicity in macrophage, and (4) macrophage cell viability and apoptosis. This article is a review of up-to-date knowledge of in vitro studies involving macrophages, and assesses endpoints of macrophage toxicity with an emphasis on (1) dissolution, (2) scanning electron microscopy analysis, (3) cytotoxicity, and (4) gene expression.